A hallmark of Alzheimer's disease is the progressive appearance of hyper-phosphorylated tau protein, tau neurofibrillary tangles, and neuron loss in the memory-processing circuits including the hippocampus. The functional changes and adaptations in these altered neural circuits are what ultimately give rises to the cognitive symptoms such as memory loss. However, it is unknown what functional changes occur in the hippocampus of the living brain with ongoing tau pathology and what pathological features causes these changes. The development of tauopathy mouse models and the tetrode recording technique, which can record hippocampal neurons in freely moving mice, make it possible to address this question. This proposal will apply the tetrode technique to a tauopathy mouse model, the transgenic rTau4510 mice, in which the over- expression of a mutated version of human tau leads to age-dependent memory deficits. We focus on a hypothesis that tau pathology in this model disrupts neural mechanisms for memory consolidation and the disruption results in unstable hippocampal memory representations. Hippocampal neurons and local field potentials will be recorded while mice perform spatial navigation tasks and while they rest. The tau pathology in the recorded brains will be subsequently examined by biochemical and immunohistochemical methods. We will investigate how the electrophysiological markers related to memory consolidation, including ripples, neuronal synchrony, and place field stability, are altered at various pathological stages in the rTg4510 mice, and which pathological parameters are critical for these electrophysiological alterations. PUBLIC HEALTH RELEVANCE: This project studies how the pathological changes in the brain give rise to the loss of memory in mice with Alzheimer's disease-like symptoms. The outcome will advance our understanding of the causes of Alzheimer's disease symptoms and generate insights into novel intervention strategies.